Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
  • A61M5/178—Syringes
  • A61M5/19—Syringes having more than one chamber, e.g. including a manifold coupling two parallelly aligned syringes through separate channels to a common discharge assembly
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/27—Growth hormone [GH], i.e. somatotropin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

• the present invention relates to a method for the production of a one-dose syringe comprising a freeze-dried protein in a first chamber and a an aqueous reconstitution solution in a second chamber characterized by the steps of filling the first chamber with a composition comprising a protein in an amount of less than 1.4 mg, amino acid and stabilizer where the weight ratio between protein and amino acid versus stabilizer is less than 1.5 , freeze-drying the first chamber to form the cake in which the ratio of the weight of the dry component versus the cake volume in the first chamber is above 12 mg/ml and filling the second chamber with an aqueous reconstitution solution with an injectable volume of less than 0.5 ml.
• Proteins which often are sensitive to storage in liquids, are normally freeze-dried and reconstituted by the patient shortly before injection.
• a device for preparation of an injectable solution of substances sensitive to degradation is described in US4968 299, and which is named KabiPen® on the market.
• KabiPen® the patient has got a device which is rather simple to handle.
• the device comprises a two-chamber ampoule Genomix® containing hGH (human Growth Hormone) as a lyophilized powder in one of the compartments and a reconstitution solution in the other.
• the patient reconstitutes the product before use.
• the reconstituted product is then stable for 3 weeks when stored at 2-8°C.
• This device is a multiple-dose syringe.
• a stabilized formulation of hGH comprising glycine, mannitol and a buffer is disclosed and in a preferred embodiment a non-ionic surfactant such as polysorbate 80 is added.
• Sodium-phosphate is suggested as buffer substance.
• the formulation has an increased stability in a lyophilized formulation and upon reconstitution. The final ratio of the ingredients is obtained by buffer exchange on a gel filtration column.
• mannitol is generally mentioned as carrier for stability of GH and IGF.
• the present invention relates thus to a method for the production of a prefilled one-dose syringe comprising a freeze-dried protein in first chamber and a an aqueous reconstitution solution in a second chamber characterized by the steps of filling the first chamber with a composition comprising a protein in an amount of less than 1.4 mg, stabilizer and amino acid where the weight ratio between protein and amino acid versus stabilizer is less than 1.5 freeze-drying the first chamber to form the cake in which the ratio of the weight of the dry component versus the cake volume is above 12 mg/m, and filling the second chamber with an aqueous reconstitution solution with an injectable volume of less than 0.5 ml.
• This claimed new device with the new composition can be produced without complications and stored with good stability
• the weight ratio between protein and amino acid versus stabilizer is preferably equal to or less than 1.3.
• the aqueous reconstitution solution has preferably an injectable volume of less than 0.3 ml.
• the solution may contain a preservative and or a buffer.
• stabilizer is meant a bulking agent matrix builder and/or cake former, e.g. mannitol but not an amino acid and by amino acid is preferably glycine used but other amino acids such as alanine can also be used.
• isotonic agent a substance for achieving the right osmolality of the injection solution.
• the protein is preferably growth hormone, recombinant or nature, which can be both human and animal such as human growth hormone (hGH), bovine growth hormone (bGH) and porcine growth hormone (pGH).
• hGH human growth hormone
• bGH bovine growth hormone
• pGH porcine growth hormone
• HGH is a protein consisting of a single chain of 191 amino acids. The molecule is crosslinked by two disulphide bridges and the monomeric form has a molecular weight of 22 kDa.
• hGH is used to stimulate linear growth in patients with hypo pituitary dwarfism or Turner's syndrome but other indications have also been suggested.
• hGH is used to stimulate linear growth in patients with hypo pituitary dwarfism or Turner's syndrome but other indications have also been suggested.
• the solution of hGH for filling is obtained from the final gel filtration step of the bulk solution purification process. Buffer is added for adjustement of the final excipient concentration and thereafter the solution is diluted with buffer to the correct protein concentration.
• cake volume is meant dispensed volume before freeze-drying.
• the solvent used is water.
• Examples F, I and K are according to the invention.
• Formulation A B First chamber, mg / cylinder GH 0,35 0,34 Glycine 0,19 0,23 Mannitol 0,95 1,14 Sodium phosphate 0,02 0,05 Disodium phosphate 0,01 0,03 Cake volume, ml 0,25 0,3 Weight of dry substances, mg 1,5 1,8 Ratio weight/cake volume 6,1 6,0 Weight ratio GH+Glycine 0,539 0,570 Mannitol 0,950 1,140 (GH+Glycine):Mannitol 0.567 0.5 Cake observation Blow out Blow out Blow out

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Medicinal Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Endocrinology (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Zoology (AREA)
• Dermatology (AREA)
• Molecular Biology (AREA)
• Gastroenterology & Hepatology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Immunology (AREA)
• Biochemistry (AREA)
• Anesthesiology (AREA)
• Vascular Medicine (AREA)
• Hematology (AREA)
• Biomedical Technology (AREA)
• Heart & Thoracic Surgery (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicinal Preparation (AREA)
• Infusion, Injection, And Reservoir Apparatuses (AREA)
• Materials For Medical Uses (AREA)
• Polysaccharides And Polysaccharide Derivatives (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Peptides Or Proteins (AREA)

Applications Claiming Priority (3)

Publications (2)

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ID=20409182

Family Applications (1)

Country Status (23)

Families Citing this family (11)

Family Cites Families (10)

• 1997
  • 1997-11-28 SE SE9704405A patent/SE9704405D0/xx unknown
• 1998
  • 1998-11-19 DE DE69837159T patent/DE69837159T2/de not_active Expired - Lifetime
  • 1998-11-19 PT PT98957272T patent/PT1034007E/pt unknown
  • 1998-11-19 JP JP2000522963A patent/JP4564652B2/ja not_active Expired - Lifetime
  • 1998-11-19 DK DK98957272T patent/DK1034007T3/da active
  • 1998-11-19 PL PL340731A patent/PL193243B1/pl not_active IP Right Cessation
  • 1998-11-19 RU RU2000116647/14A patent/RU2214285C2/ru not_active IP Right Cessation
  • 1998-11-19 AU AU13566/99A patent/AU742494B2/en not_active Ceased
  • 1998-11-19 CN CNB988115921A patent/CN1156315C/zh not_active Expired - Fee Related
  • 1998-11-19 KR KR1020007005756A patent/KR100567358B1/ko not_active Expired - Fee Related
  • 1998-11-19 MX MXPA00005214A patent/MXPA00005214A/es not_active IP Right Cessation
  • 1998-11-19 ES ES98957272T patent/ES2281142T3/es not_active Expired - Lifetime
  • 1998-11-19 CA CA002311754A patent/CA2311754C/en not_active Expired - Lifetime
  • 1998-11-19 SK SK720-2000A patent/SK285668B6/sk not_active IP Right Cessation
  • 1998-11-19 WO PCT/SE1998/002096 patent/WO1999027983A1/en not_active Ceased
  • 1998-11-19 AT AT98957272T patent/ATE354390T1/de not_active IP Right Cessation
  • 1998-11-19 HU HU0004410A patent/HUP0004410A3/hu unknown
  • 1998-11-19 NZ NZ505150A patent/NZ505150A/xx unknown
  • 1998-11-19 CZ CZ20001948A patent/CZ300255B6/cs not_active IP Right Cessation
  • 1998-11-19 EP EP98957272A patent/EP1034007B1/en not_active Expired - Lifetime
  • 1998-11-20 US US09/196,514 patent/US6152897A/en not_active Expired - Lifetime
• 2000
  • 2000-05-29 NO NO20002754A patent/NO324692B1/no not_active IP Right Cessation
• 2007
  • 2007-03-20 CY CY20071100395T patent/CY1106403T1/el unknown

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